US3682896A - Preparation of 6-acylaminopenicillanic acids - Google Patents

Preparation of 6-acylaminopenicillanic acids Download PDF

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US3682896A
US3682896A US10286A US3682896DA US3682896A US 3682896 A US3682896 A US 3682896A US 10286 A US10286 A US 10286A US 3682896D A US3682896D A US 3682896DA US 3682896 A US3682896 A US 3682896A
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mol
acetone
treated
sodium
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US10286A
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Kenneth David Hardy
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Beecham Group PLC
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Beecham Group PLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • 6-aminopenicillanic acid and 6-acylaminopenicillanic acids are prepared free from immunogenic macromolecules, for use in producing semi-synthetic penicillins, by a reaction under anhydrous conditions avoiding the use of enzymes and without hydrolytic cleavage of the 5- lactam ring structure.
  • the preferred process includes the use of a nucleophile in at least a catalytic amount for treating the starting material.
  • a substance may also be employed which is both a nucleophile and an acid acceptor.
  • This invention relates to the preparation of penicillanic acids and is particularly concerned with the preparation of 6-aminopenicillanic acid and penicillins from N-(6- aminopenicillanoyloxy) imines or N-(6-substituted penicillanoyloxy) irnines.
  • An advantage of the present invention is that the reaction takes place under anhydrous conditions and thus there is no danger of hydrolytic cleavage of the sensitive S-lactam ring of the compounds involved.
  • 0N-- HCO-ON CHR (II) or its acid addition salt wherein R is an alkyl, aryl or heterocyclic group in an organic solvent or mixture of organic solvents with an acid acceptor.
  • the acid acceptor may be a source of alkali metal ions or a tertiary amine, e.g. triethylamine, and it is preferably employed in at least one molecular proportion.
  • the group R in Formula II may be an alkyl group, especially an alkyl group having from 1 to 6 carbon atoms such as, methyl, ethyl, propyl or butyl; an aryl group such as phenyl; a heterocyclic group, particularly a monocyclic heterocyclic group such as pyridyl or furfuryl.
  • the compound (II) is treated with a nucleophile in addition to the acid acceptor, said nucleophile being present in at 3,682,896 Patented Aug. 8, 1972 least a catalytic amount.
  • nucleophile may be used, particularly suitable ones being thiols, the thiocyanate ion and the iodide ion.
  • a single substance may be employed which functions as both acid acceptor and nuleophile.
  • An example of one such substance is sodium thiophenoxide, which provides sodium ions as the acid acceptor and Ph& ions as the nucleophile.
  • X in the above general formulae is an acyl group it is particularly convenient to select the solvents and reagents in such a way that a salt of the resulting penicillanic acid (I) crystallizes from the mixture, either directly or after the addition of another suitable solvent. It is in fact one function of the acid acceptor to provide the cation of such a salt.
  • the reagents are triethylamine and a catalytic amount of thiophenol then, provided the solvent has been suitably chosen, the triethylamine salt of the penicillin crystallizes.
  • the nature of the solid product will depend on the solubilities of the two penicillin salts in the particular solvent ssytem.
  • a bermylpenicillin derivative in acetone is treated with one molecular proportion each of triethylamine and potassium thiocyanate it is found in practice that the crystalline product is the potassium rather than the triethylamine salt of benzylpenicillin.
  • the desired cleavage reaction takes place but no product crystallizes, in which case other procedures must be adopted to recover the product.
  • One such procedure is to remove all or part of the organic solvent in vacuo, dilute the residue with water, and adjust to a suitable pH.
  • this pH may be low (about 2) and the free acid form of the penicillin may be extracted into a suitable organic solvent, and recovered therefrom by conventional means.
  • X is hydrogen
  • a suitable pH is in the neighborhood of the isoelectric point of 6APA (i.e. about 4.3), so that this product may crystallize directly from the aqueous solution.
  • the solution was treated with 1.67 N sodium 2-ethylhexoate in methyl isobutyl ketone (0.6 m1., 0.001 mol.) followed by 2-ethyl hexoic acid (0.16 ml., 0.001 mol.) and evaporated under reduced temperature and pressure.
  • the residual yellow oil was dissolved in methyl isobutyl ketone saturated with water (40 ml.), diluted with dry methyl isobutyl ketone (60 ml.) and stirred at room temperature for 1 /2 hours.
  • the crystalline solid produced was filtered off, washed with methyl isobutyl ketone and dried in vacuo to give the penicillin monohydrate 0.3 g. (63.1%) as a colorless crystalline solid identical with authenic material by infrared spectra.
  • EXAMPLE 4 Sodium u-phenoxyethyl penicillin N-[6 (on phenoxypropionamido)penicillanoyloxy]- Z-furfurylidene imine (0.46 g., 0.001 mol.), dissolved in a mixture of dimethyl formamide (1 ml.) and thiophenol (1 drop), was treated with triethylamine (0.14 ml.) and stood at room temperature for 2 hours. The reaction solution was treated with 1.67 N sodium 2- ethylhexoate in methyl isobutyl Igetone. ,0.6 ml.) and evaporated under reduced temperature and pressure.
  • N [6 (phenylacetamido)penicillanoyloxy]ben zylidene imine (2.14 g., 0.005 mol.) was added to a solution of sodium thiocyanate (0.41 g., 0.005 mol.) in dry acetone (5 ml.) and treated with triethylamine (0.7 ml.). The mixture was stirred at room temperature for 2% hours. The solid product was filtered off, washed well with acetone and dried in vacuo to give a colorless crystalline solid 1.15 g. (64.6%) shown to be identical with authentic sodium benzylpenicillin by infra-red spectra.
  • EXAMPLE 7 Benzylpenicillin potassium salt N [6 (phenylacetamido)penicillanoyloxy]benzylidene imine (2.14 g., 0.005 mol.) was added to a solution of potassium thiocyanate (0.49 g., 0.005 mol.) in dry acetone (10 ml.) and treated with triethylamine (0.7 ml.). The mixture was stirred at room temperature for 4 hours. The solid product was filtered oflf, washed well with acetone to give a colorless crystalline solid 1.38 g. (74.2%) shown to be identical with authentic potassium benzylpenicillin by infra-red spectra.
  • EXAMPLE 9 Sodium 2.6-dimethoxyphenylpenicillin (a) N- 6-(2,6-dimethoxybenzamido)penicillanoyloxy]- 2-furfurylidene imine (0.47 g., 0.001 mol.) in a mixture of dimethylformamide (1 ml.) and thiophenol (1 drop) was treated with triethylamine (0.14 ml.) and stood at room temperature for 2 hours. The yellow solution was treated with 1.67 N sodium 2-ethylhexoate in methyl isobutyl ketone (0.6 m1.) and evaporated under reduced temperature and pressure.
  • EXAMPLE 11 Sodium benzylpenicillin N ['6 (phenylacetamido)pencillanoyloxy]pyridine-4- ylidene imine (2.19 g., 0.005 mol.) in dry acetone (20 ml.) was treated with a solution of sodium iodide (0.75 g., 0.005 mol.) in dry acetone (10 ml. followed bytriethylamine (0.7 ml.) as described in Example 6(a) to give a colorless crystalline solid 0.56 g. (31.5%) shown to be identical with authentic material by infra-red spectra.
  • EXAMPLE 13 Sodium benzylpenicillin N-[6 (phenylacetamido)pencillanoyloxy]butyrylidene imine (0.8 g., 0.002 mol.) in dry acetone (10 ml.) was treated with a solution of sodium iodide (0.3 g.) in dry acetone (5 ml.) followed by triethylamine (0.28 ml.) as described in Example 6(a) to give a colorless crystalline solid 0.16 g. (22.5%) shown to be identical with authentic material by infra-red spectra.
  • EXAMPLE 14 6-aminopenicillanic acid N-(6-aminopenicillanoyloxy)benzylidene imine p-toluene sulphonate (0.49 g., 0.001 mol.) in diethylformamide (1 ml.) was treated with triethylamine (0.28 ml.) and thiophenol (2 drops) and stood at room temperature for 4 hours. The solution was diluted with water (5 ml.) and washed with ether (2X 5 ml.). The clear aqueous layer was adjusted to pH 4 with N hydrochloric acid and stirred for 16 hours. The solid product was filtered off, washed with water, dried in vacuo to give a cream colored crystalline solid 0.09 g. (41.7%) shown to be identical with authentic 6-aminopenicillanic acid by infra-red spectra.
  • EXAMPLE 16 Sodium benzylpenicillin N [6 (phenylacetamido)penicillanoyloxy]ethylidene imine (1.28 g.) in dry acetone (20 ml.) was treated with a solution of sodium iodide (0.52 g.) in dry acetone (5 m1.) followed by triethylamine (0.5 ml.) and stirred at room temperature for 2 hours. The solid was filtered off, washed well with acetone and dried in vacuo to give a colorless crystalline solid 0.42 g. (34.6%) shown to be identical with authentic material.
  • R is lower alkyl of 1 to 6 carbon atoms, phenyl pyridyl or furfuryLin an organic solvent selected from acetone, dimethylformamide, thiophenol, ethanethiol and mixtures thereof, with sodium or potassium iodide or thiocyanate or sodium thiophenoxide, or triethylamine as acid acceptor.
  • a process according to claim 1 in which the acid acceptor is present in at least one molecular proportion. 3. A process according to claim 1, in which is further present a thiol, thiocyanate or iodide as nucleophile.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US10286A 1969-02-13 1970-02-10 Preparation of 6-acylaminopenicillanic acids Expired - Lifetime US3682896A (en)

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GB7756/69A GB1255035A (en) 1969-02-13 1969-02-13 Preparation of penicillanic acids

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US (1) US3682896A (de)
AT (1) AT293619B (de)
BE (1) BE745901A (de)
BR (1) BR7016628D0 (de)
CH (1) CH544772A (de)
DE (1) DE2006199A1 (de)
ES (1) ES376436A1 (de)
FR (1) FR2034544A1 (de)
GB (1) GB1255035A (de)
IE (1) IE33955B1 (de)
NL (1) NL7001685A (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3948927A (en) * 1972-04-10 1976-04-06 Queen's University 2,2-Dimethyl-3R-carboxy-6S-amino-1-oxa-4-aza-5R-bicyclo-[3,2,0]heptan-7-one

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1670103U (de) 1952-05-21 1954-01-14 Hagenuk Hanseatische Appbau Ge Anzeigeeinrichtung mit zwei achsengleichen zeigern.
DE1937962U (de) 1965-02-19 1966-05-05 Porsche Kg Anordnung zur axialsicherung des abtriebskegelrades eines ausgleichsgetriebes.

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3948927A (en) * 1972-04-10 1976-04-06 Queen's University 2,2-Dimethyl-3R-carboxy-6S-amino-1-oxa-4-aza-5R-bicyclo-[3,2,0]heptan-7-one

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BE745901A (fr) 1970-08-12
CH544772A (de) 1973-11-30
GB1255035A (en) 1971-11-24
AT293619B (de) 1971-10-25
DE2006199A1 (de) 1970-09-03
ES376436A1 (es) 1972-04-16
BR7016628D0 (pt) 1973-06-07
NL7001685A (de) 1970-08-17
FR2034544A1 (de) 1970-12-11
IE33955B1 (en) 1974-12-30
IE33955L (en) 1970-08-13

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